US4611068A - Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein - Google Patents

Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein Download PDF

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Publication number
US4611068A
US4611068A US06/673,231 US67323184A US4611068A US 4611068 A US4611068 A US 4611068A US 67323184 A US67323184 A US 67323184A US 4611068 A US4611068 A US 4611068A
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US
United States
Prior art keywords
formula
compound
hydrogen
alkyl
chloro
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Expired - Fee Related
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US06/673,231
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English (en)
Inventor
Yvan Guindon
Howard E. Morton
Christiane Yoakim
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Merck Frosst Canada and Co
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Merck Frosst Canada and Co
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Application filed by Merck Frosst Canada and Co filed Critical Merck Frosst Canada and Co
Priority to US06/673,231 priority Critical patent/US4611068A/en
Priority to EP85114399A priority patent/EP0183132B1/en
Priority to CA000495158A priority patent/CA1245226A/en
Priority to DE8585114399T priority patent/DE3573780D1/de
Priority to JP60257902A priority patent/JPS61129178A/ja
Assigned to MERCK FROSST CANADA, INC. reassignment MERCK FROSST CANADA, INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: YOAKIM, CHRISTIANE, GUINDON, YVAN, MORTON, HOWARD E.
Application granted granted Critical
Publication of US4611068A publication Critical patent/US4611068A/en
Priority to CA000546907A priority patent/CA1273352A/en
Priority to CA000546908A priority patent/CA1307534C/en
Priority to US07/176,828 priority patent/US4855481A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • This invention relates to a novel process for the preparation of antihypercholesterolemic agents of the following general structural formula (I): ##STR2## wherein R 1 is selected from the group consisting of: ##STR3## wherein Q is ##STR4## R 6 is H or OH; R is hydrogen or methyl, and a, b, c, and d represent optional double bonds except when a and c are double bonds, R 6 is not OH, especially wherein b and d represent double bonds or a, b, c, and d are all single bonds; or ##STR5## wherein R 2 and R 3 are independently C 1-3 alkyl or halo (F, Cl or Br) and R 4 is hydrogen, phenyl, benzyloxy, substituted phenyl or substituted benzyloxy in which the phenyl group in each case is substituted with one or more substituents selected from C 1-3 alkyl and halo, which comprises:
  • X is a metal atom or metal complex selected from Li, MgCl, MgBr, (CuMgCl) 1/2 or (CuMgBr) 1/2 or an alkali metal (Li, Na, or K) plus an aryl sulfonyl group selected from ##STR7## followed by the removal of the aryl sulfonyl group [Trost et al.
  • the compounds prepared by the process of this invention are those compounds of the formula (I) wherein R 1 is (a) and R 6 is hydrogen and R is hydrogen or methyl and b and d represent double bonds or a, b, c and d are single bonds.
  • the compounds prepared by the process of this invention are those compounds of the formula (I) wherein R 1 is (b), R 2 and R 3 independently are chloro, fluoro or methyl and R 4 is hydrogen, 4-fluoro-3-methylphenyl or 4-fluorobenzyloxy.
  • R 1 is (b)
  • R 2 and R 3 independently are chloro, fluoro or methyl
  • R 4 is hydrogen, 4-fluoro-3-methylphenyl or 4-fluorobenzyloxy.
  • the most preferred compounds are those wherein (1) R 2 and R 3 are methyl and R 4 is 4-fluoro-3-methylphenyl; (2) R 2 and R 3 are methyl and R 4 is 4-fluorobenzyloxy; and (3) R 2 and R 3 are chloro and R 4 is hydrogen.
  • the reaction of the compound of the formula (II) with the compound of the formula (III) is conducted at a temperature between -78° and 0° C., preferably at -78° C. with warming to -20° C. for a period of from 1 to 12 hours, most preferably 1 hour at -78° C. and 1 hour at -23° C., in an inert solvent.
  • inert solvents are: ethers or thioethers or mixtures thereof, such as diethyl ether, tetrahydrofuran, dimethoxyethane, dimethylsulfide and the like.
  • the amounts of reactants that are employed in this reaction may vary between 0.1 and 1.0 equivalents of the compound of the formula (II) to each equivalent of the compound of the formula (III). However, 0.4 equivalents of the compound of the formula (II) is preferred.
  • the compound of the formula (III) wherein X is (CuMgBr) 1/2 is a preferred reactant.
  • the lactonization of the compound of the formula (IV) is conducted at a temperature between 0° and 25° C., preferably at ambient temperature, for a period of from 1 to 12 hours, preferably 3 hours in an inert solvent with a catalytic amount of an acid.
  • inert solvents include: hydrocarbons, such as, hexane, toluene, benzene, cyclohexane and the like; and ethers, such as, diethylether, tetrahydrofuran, dimethoxyethane and the like.
  • Such acids are organic acids, such as, p-toluenesulfonic, benzenesulfonic and the like and inorganic acids, such as, hydrochloric.
  • organic acids such as, p-toluenesulfonic, benzenesulfonic and the like
  • inorganic acids such as, hydrochloric.
  • the preferred acid utilized in the lactonization is p-toluenesulfonic acid.
  • the removal of the R 7 protecting group is conducted at a temperature between -78° and 0° C., preferably at -78° C. for a period from 1 to 12 hours, preferably 1 hour in an inert solvent in the presence of an organoboron halide.
  • inert solvents include: chlorinated hydrocarbons, such as, methylene chloride, chloroform, dichloroethane or low melting mixtures thereof and the like.
  • the organoboron halide reactant is represented by the following formula:
  • R 8 and R 9 independently are C 1-4 alkyl, phenyl or when taken together with the boron atom to which they are attached from a 5, 6 or 7 membered ring or a bicyclic ring and Y is chloro or bromo.
  • the preferred organoboron halide is dimethylboron bromide.
  • the amount of the organoboron halide utilized may vary between 1 and 10 equivalents for each equivalent of the compound of the formula (V), with 4 equivalents being preferred.
  • the starting materials are either known or readily prepared according to the synthetic pathways described below.
  • (S)-Malic acid (1) is reduced under standard reduction conditions using BH 3 .THF and then ketalized with acetone to give compound (2).
  • Compound (2) is subjected to a Swern oxidation to yield compound (3), which, without isolation, is treated under Wittig conditions with Ph 3 PCHCO 2 R 5 to give Compound (4).
  • Compound (4) is hydrolyzed under acid conditions and selectively protected to give Compound (5) wherein Pr is a protecting group selected from benzoyl, acetyl, triphenylsilyl or tert-butyldiphenylsilyl, preferably t-butyldiphenylsilyl.
  • Compound (5) is cyclized to Compounds (6) and (7) under basic conditions with concomitant migration of the Pr group.
  • Compound (7) may be isomerized to the desired Compound (6) under basic conditions.
  • Compound (6) is converted to Compound (8) using an organoboron halide R 8 R 9 BY, preferably dimethylboron bromide.
  • Compound (8) is treated with R 7 -halide to get Compound (9) which is treated with tetraalkylammonium fluoride or an alkalimetal alkoxide to afford the compound of formula (II).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Epoxy Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Steroid Compounds (AREA)
US06/673,231 1984-11-19 1984-11-19 Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein Expired - Fee Related US4611068A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US06/673,231 US4611068A (en) 1984-11-19 1984-11-19 Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein
CA000495158A CA1245226A (en) 1984-11-19 1985-11-13 METHOD FOR THE PREPARATION OF HMG-COA REDUCTASE INHIBITORS AND INTERMEDIATE COMPOUNDS
DE8585114399T DE3573780D1 (en) 1984-11-19 1985-11-13 A process for the preparation of hmg-coa reductase inhibitors and intermediate compounds employed therein
EP85114399A EP0183132B1 (en) 1984-11-19 1985-11-13 A process for the preparation of hmg-coa reductase inhibitors and intermediate compounds employed therein
JP60257902A JPS61129178A (ja) 1984-11-19 1985-11-19 ＨＭＧ‐ＣｏＡ還元酵素阻害剤及びそれに使用する中間体化合物の製造方法
CA000546907A CA1273352A (en) 1984-11-19 1987-09-15 Intermediates useful in the preparation of hmg-coa reductase inhibitors
CA000546908A CA1307534C (en) 1984-11-19 1987-09-15 Intermediates useful in the preparation of hmg-coa reductase inhibitors
US07/176,828 US4855481A (en) 1984-11-19 1988-04-04 Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US06/673,231 US4611068A (en) 1984-11-19 1984-11-19 Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein

Related Child Applications (1)

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US87584686A Division 1984-11-19 1986-06-18

Publications (1)

Publication Number Publication Date
US4611068A true US4611068A (en) 1986-09-09

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US06/673,231 Expired - Fee Related US4611068A (en) 1984-11-19 1984-11-19 Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein

Country Status (5)

Country Link
US (1) US4611068A (enrdf_load_stackoverflow)
EP (1) EP0183132B1 (enrdf_load_stackoverflow)
JP (1) JPS61129178A (enrdf_load_stackoverflow)
CA (1) CA1245226A (enrdf_load_stackoverflow)
DE (1) DE3573780D1 (enrdf_load_stackoverflow)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4719229A (en) * 1987-05-13 1988-01-12 Merck & Co., Inc. Antihypercholesterolemic agents
US4870199A (en) * 1986-04-30 1989-09-26 Sandoz Pharm. Corp. Processes for the synthesis of diprotected R[R*,S*]-3,5-dihydroxy-6-oxohexanoate esters
US4916239A (en) * 1988-07-19 1990-04-10 Merck & Co., Inc. Process for the lactonization of mevinic acids and analogs thereof
US4970231A (en) * 1989-06-09 1990-11-13 Merck & Co., Inc. 4-substituted HMG-CoA reductase inhibitors
US5102911A (en) * 1989-06-09 1992-04-07 Merck & Co, Inc. 4-Substituted HMG-CoA reductase inhibitors
US5430171A (en) * 1992-06-02 1995-07-04 Takasago International Corporation T-butyl (R)-(-)-4-cyano-3-hydroxybutyrate and process for preparing the same

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT85109A (en) * 1986-06-23 1987-07-01 Merck & Co Inc Process for the preparation of hydroxy-tetrahydropyranone derivatives or corresponding ring opened dihydroxy acids which are hmg-coa reductase inhibitors
US4845237A (en) * 1987-04-15 1989-07-04 Merck & Co., Inc. Acylation process for the synthesis of HMG-CoA reductase inhibitors
EP0306263B1 (en) * 1987-09-02 1992-03-18 Merck & Co. Inc. Novel hmg-coa reductase inhibitors
DE19714343A1 (de) * 1997-04-08 1998-10-15 Bayer Ag Chromatographische Enantiomerentrennung von Lactonen
EP3698797A1 (en) 2017-10-16 2020-08-26 Tsinghua University Mevalonic acid pathway inhibitor and pharmaceutical composition thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4375475A (en) * 1979-08-17 1983-03-01 Merck & Co., Inc. Substituted pyranone inhibitors of cholesterol synthesis
US4448979A (en) * 1980-06-06 1984-05-15 Sankyo Company, Limited ML-236B Derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ191762A (en) * 1978-10-19 1982-09-14 Merck & Co Inc Hypocholesteremic composition containing cholesterol synthesis inhibitor and anion exchange resin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4375475A (en) * 1979-08-17 1983-03-01 Merck & Co., Inc. Substituted pyranone inhibitors of cholesterol synthesis
US4448979A (en) * 1980-06-06 1984-05-15 Sankyo Company, Limited ML-236B Derivatives

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
B. M. Trost et al., Tetrahedron Letters, No. 39 (1976) pp. 3477 3478. *
B. M. Trost et al., Tetrahedron Letters, No. 39 (1976) pp. 3477-3478.
C. Huynh et al., Tetrahedron Letters, No. 17 (1979) pp. 1503 1506. *
C. Huynh et al., Tetrahedron Letters, No. 17 (1979) pp. 1503-1506.
Herr et al., Jour. Am. Chem. Soc., vol. 92:12, Jun. 17, 1970, pp. 3813 3814. *
Herr et al., Jour. Am. Chem. Soc., vol. 92:12, Jun. 17, 1970, pp. 3813-3814.
Herr et al., Jour. Am. Chem. Soc., vol. 92:16, Aug. 12, 1970, pp. 4979 4981. *
Herr et al., Jour. Am. Chem. Soc., vol. 92:16, Aug. 12, 1970, pp. 4979-4981.
I. T. Harrison et al., Compendium of Organic Synthetic Methods (1971), pp. 81 and 138. *
M. S. Kharasch et al., Grignard Reactions of Nonmetallic Substances, (1954), pp. 961 963. *
M. S. Kharasch et al., Grignard Reactions of Nonmetallic Substances, (1954), pp. 961-963.
N. G. Gaylord et al., Chem. Rev., vol. 49 (1951), pp. 413 415; 424 431. *
N. G. Gaylord et al., Chem. Rev., vol. 49 (1951), pp. 413-415; 424-431.
Paul C. Anderson et al., Tetrahedron Letters, vol. 24 (13) (1983) pp. 1373 1376. *
Paul C. Anderson et al., Tetrahedron Letters, vol. 24 (13) (1983) pp. 1373-1376.
Raymond L. Funk et al., Tetrahedron Letters, vol. (16) (1984) pp. 1655,1658. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4870199A (en) * 1986-04-30 1989-09-26 Sandoz Pharm. Corp. Processes for the synthesis of diprotected R[R*,S*]-3,5-dihydroxy-6-oxohexanoate esters
US4719229A (en) * 1987-05-13 1988-01-12 Merck & Co., Inc. Antihypercholesterolemic agents
US4916239A (en) * 1988-07-19 1990-04-10 Merck & Co., Inc. Process for the lactonization of mevinic acids and analogs thereof
US4970231A (en) * 1989-06-09 1990-11-13 Merck & Co., Inc. 4-substituted HMG-CoA reductase inhibitors
US5102911A (en) * 1989-06-09 1992-04-07 Merck & Co, Inc. 4-Substituted HMG-CoA reductase inhibitors
US5430171A (en) * 1992-06-02 1995-07-04 Takasago International Corporation T-butyl (R)-(-)-4-cyano-3-hydroxybutyrate and process for preparing the same

Also Published As

Publication number Publication date
DE3573780D1 (en) 1989-11-23
EP0183132A2 (en) 1986-06-04
EP0183132B1 (en) 1989-10-18
CA1245226A (en) 1988-11-22
CA1273352C (enrdf_load_stackoverflow) 1990-08-28
EP0183132A3 (en) 1987-06-16
JPS61129178A (ja) 1986-06-17

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